MET fusions and splicing variants convergently defne a subgroup of glioma sensitive to MET inhibitors  

作　　者：Ke-Nan Zhang Zheng Zhao Jing Chen Zhaoshi Bao Rui-Chao Chai Zhiyan Sun Lingxiang Wu Zhiliang Wang Hanjie Liu Quanhua Mu Huimin Hu Fan Zeng Zheng Wang Guanzhang Li Yuanhao Chang Qiangwei Wang Fan Wu Ying Zhang Yuqing Liu Chunjie Jiang Ulf Dietrich Kahlert Do-Hyun Nam Wei Zhang Chunsheng Kang Jiguang Wang Rongjie Tao Qianghu Wang Tao Jiang 

机构地区：[1]Beijing Neurosurgical Institute,Capital Medical University,Beijing,China [2]Department of Neurosurgery,Beijing Tiantan Hospital,Capital Medical University,Beijing,China [3]Department of Bioinformatics,Nanjing Medical University,Nanjing,Jiangsu,China [4]Department of Chemical and Biological Engineering,Divison of Life Science,Center for Systems Biology and Human Health,and State Key Laboratory of Molecular Neuroscience,The Hong Kong University of Science and Technology,Hong Kong,China [5]Division of Diabe‑tes,Endocrinology,and Metabolism,Department of Medicine,Baylor College of Medicine,Houston,TX,USA [6]Molecular and Experimental Surgery,Faculty of Medicine and University Medicine Magdeburg,Magdeburg,Germany [7]Institute for Refractory Cancer Research,Samsung Medical Center,Seoul,Republic of Korea [8]Department of Health Science&Technology,Samsung Advanced Institute for Health Sciences&Technology(SAIHST),Sungkyunkwan University,Seoul,Republic of Korea [9]Department of Neurosurgery,Samsung Medical Center,Sungkyunkwan University School of Medicine,Seoul,Republic of Korea [10]Laboratory of Neuro‑Oncology,Ministry of Education and Tianjin City,Tianjin Neurological Institute,Tianjin Medical University General Hospital,Key Laboratory of Post,Neuro Injury Neuro-Repair and Regeneration in Central Nervous System,Tianjin,China [11]Departments of Neurosurgery,Shandong Cancer Hospital and Institute,Shandong University,Jinan,Shandong,China [12]Center of Brain Tumor,Beijing Institute for Brain Disorders,Beijing,China [13]China National Clinical Research Center for Neurological Diseases,Beijing,China [14]Research Unit of Accurate Diagnosis,Treatment,and Translational Medicine of Brain Tumors,Chinese Academy of Medical Sciences,Beijing,China

出　　处：《Holistic Integrative Oncology》2022年第1期244-254,共11页整合肿瘤学（英文）

基　　金：supported by grants from the Natural Science Foundation of China (NSFC)/Research Grants Council (RGC),Hong Kong,China Joint Research Scheme (81761168038);the National Natural Science Foundation of China (81802994,81903078,81972337,81972816,82002647,82192894,82103623,and 82002994);the Mainland-Hong Kong Joint Funding Scheme ITC grant MHP/004/19 and MOST grant 2019YFE0109400;the Beijing Natural Science Foundation (JQ20030);Sino-German Center for Research Promotion (M-0020);the Beijing Nova Program (Z201100006820118).

摘　　要：Purpose:Our previous study has shown that PTPRZ1-MET(ZM)fusion is a viable target for MET inhibitors in gliomas.However,the diversity and prevalence of somatic MET alterations in difuse gliomas are still elusive and need to be extensively characterized for identifying novel therapeutic targets.Methods:Totally,1,350 glioma patients and 31 patient-derived cells were collected from the Chinese Glioma Genome Atlas(CGGA)and published data.All kinds of MET fusions and/or splicing variants(MET F/SVs)were identifed by bioinformatical methods.Single-cell RNA sequencing(scRNA-seq)were used for validation.In vitro experiments of drug resistance were conducted for the possibility of MET-targeted treatment.Results:MET F/SVs but not genomic amplifcation,were highly enriched in the secondary glioblastomas(sGBM)and marked worse prognosis.Further molecular and scRNA-seq analysis revealed that MET F/SVs were induced in the course of glioma evolution and highly associated with MET overexpression.Subsequent in vitro and the clinical study showed that cells and patients harboring MET F/SVs have better response to MET inhibitors.Conclusion:Our fndings expanded the percentage of gliomas with abnormal MET alterations and suggested that a subgroup of gliomas harboring MET F/SVs may beneft from MET-targeted therapy.

关 键 词：MET variation Secondary glioblastoma Biomarker MET inhibitor Precision neuro-oncology 

分 类 号：R739.41[医药卫生—肿瘤]